The present invention relates to cephem compounds having a broad antibacterial spectrum over various pathogenic bacteria and to pharmaceutical compositions containing the same. The compounds of the present invention are particularly efficacious against MRSA (methicillin resistant S. aureus).
Study of so-called broad spectrum cephem compounds having potent antibacterial activities against various Gram-positive and Gram-negative bacteria has recently been focused on cephem compounds at which 7-side chain is substituted with aminothiazole or aminothiadiazole and 3-position with a cyclic-type quarternary ammoniummethyl group. For example, the known 7-aminothiazole types include cefepime hydrochloride (U.S. Pat. No. 4,406,899), cefpirome sulfate (U.S. Pat. No. 4,609,653, JP(A) S57-192394), and cefoselis sulfate (JP(A) H07-196665, WO97/41128), and the 7-aminothiadiazole types include cefclidin (U.S. Pat. No. 4,748,171), and cefozopran hydrochloride (U.S. Pat. No. 4,864,022, JP(A) S62-149682, JP(A) H03-47189). These cephem compounds show almost none or extremely weak activities against MRSA which has been a clinical concern.
The other documents, disclosing the same types of cephem compounds, include, for example, JP(A) 4789/1983, JP(A) 155183/1985, JP(A) 97982/1985, JP(A) 97983/1985, JP(A) 24389/1982, JP(A) 57390/1983, JP(B) 65350/1991, JP(B) 14117/1992, JP(A) 231684/1985, JP(A) 30786/1987, WO92/22556, JP(A) 222058/1993, JP(A) 157542/1994, JP(A) 101958/1995, and JP(A) 101960/1995.
Among them, JP(A) 4789/1983 discloses cephem compounds which have an optionally substituted and 2 or more N atoms-containing heterocycle cation at the 3-position. JP(A) 155183/1985 discloses cephem compounds which have a 2 or more N atoms-containing and unsaturated condensed heterocycle cation at the 3-position. These documents, however, describe or suggest no concrete embodiment of a cephem compound having an imidazopyridiniummethyl group at the 3-position.
Though JP(A) 105685/1985, equivalent to J. Med. Chem. 1990, 33, P2114-2121 discloses cephem compounds having an imidazopyridiniummethyl group at the 3-position, any of the 3-substituents of the working example compounds is limited to imidazo[4,5-c]pyridiniummethyl. On the other hand, a compound having an imidazo[4,5-b]pyridiniummethyl group at the 3-position is shown by the chemical name without any physical data or the like. Further, the [4,5-b]-type compounds have only aminothiazole group as part of the 7-side chain. Namely, the document does not concretely describe a cephem compound at which 3-position is substituted with an imidazo[4,5-b]pyridiniummethyl group and 7-side chain with aminothiadiazole.
Therefore, it has been desired to develop cephem compounds of broad antibacterial spectrum which have anti-MRSA activity applicable enough to clinical use.
The present inventors have intensively studied to find out that introduction of an imidazo[4,5-b]pyridiniummethyl group into the 3-position of cephem compounds leads to broad antibacterial spectrum and excellent anti-MRSA activity, and have accomplished the present invention shown below.
(1) a compound of the formula(I): 
xe2x80x83wherein,
X is N or CY and Y is H or halogen;
R1 is amino or protected amino;
R2 is hydrogen, optionally substituted lower alkyl or optionally substituted cycloalkyl;
R3 is hydrogen, hydroxy, halogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkylthio or optionally substituted amino;
R4 is hydrogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkyl(lower)alkyl or an optionally substituted N-containing heterocyclic group;
R5 is hydrogen, amino, optionally substituted lower alkyl, optionally substituted lower alkoxy or optionally substituted lower alkylthio, or R4 and R5 taken together may form lower alkylene in which an optional hetero atom(s) intervene; and
a wavy line means syn- or anti-isomerism or a mixture thereof, an ester, a pharmaceutically acceptable salt, a prodrug, or a solvate thereof (herein after may be referred to as compound (I)).
(2) the compound described in above (1) wherein X is N.
(3) the compound described in above (1) wherein R1 is amino.
(4) the compound described in above (1) wherein R2 is hydrogen or optionally substituted lower alkyl.
(5) the compound described in above (4) wherein R2 is lower alkyl optionally substituted with halogen.
(6) the compound described in above (1) wherein R3 is hydrogen.
(7) the compound described in above (1) wherein R4 is hydrogen, optionally substituted lower alkyl or an optionally substituted N-containing heterocyclic group.
(8) the compound described in above (7) wherein R4 is hydrogen, lower alkyl optionally substituted with amino, lower alkylamino or hydroxy(lower) alkylamino, or an optionally substituted 4- to 6-membered N-containing saturated heterocyclic group.
(9) the compound described in above (1) wherein R5 is hydrogen.
(10) the compound described in above (1) wherein the wavy line means syn-isomerism.
(11) the compound described in above (1) wherein X is N; R1 is amino; R2 is hydrogen or optionally substituted lower alkyl; R3 is hydrogen; R4 is hydrogen, optionally substituted lower alkyl or an optionally substituted N-containing heterocyclic group; R5 is hydrogen; and the wavy line means syn-isomerism.
(12) the compound described in above (11) wherein X is N; R1 is amino; R2 is hydrogen or lower alkyl optionally substituted with halogen; R3 is hydrogen; R4 is hydrogen, lower alkyl optionally substituted with amino, lower alkylamino or hydroxy(lower)alkylamino, or an optionally substituted 4- to 6-membered N-containing saturated heterocyclic group; R5 is hydrogen; and the wavy line means syn-isomerism.
(13) the compound described in above (12) wherein X is N; R1 is amino; R2 is hydrogen, xe2x80x94CH3, xe2x80x94CH2F, xe2x80x94CH2CH3 or xe2x80x94CH2CH2F; R3 is hydrogen; R4 is hydrogen, xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94(CH2)2CH3, xe2x80x94(CH2)3NH2, xe2x80x94(CH2)3NHCH3, xe2x80x94(CH2)3NH(CH2)2OH, azetidinyl, pyrrolidinyl or piperidyl; R5 is hydrogen; and the wavy line means syn-isomerism.
(14) the compound described in above (13) wherein X is N; R1 is amino; R2 is hydrogen, xe2x80x94CH2F or xe2x80x94CH2CH3; R3 is hydrogen; R4 is hydrogen, xe2x80x94(CH2)3NH2, xe2x80x94(CH2)3NHCH3 or xe2x80x94(CH2)3NH(CH2)2OH; R5 is hydrogen; and the wavy line means syn-isomerism.
(15) the compound described in above (14), a pharmaceutically acceptable salt or hydrate thereof wherein X is N; R1 is amino; R2 is xe2x80x94CH2F; R3 is hydrogen; R4 is xe2x80x94(CH2)3NHCH3; R1 is hydrogen; and the wavy line means syn-isomerism.
(16) the compound described in above (15) which is a sulfate or a hydrate thereof.
(17) the compound described in any of above (1) to (16), which shows an antibacterial activity against Gram-positive bacteria including MRSA and Gram-negative bacteria.
(18) the compound described in (17) of which MIC50 value against MRSA is 50 xcexcg/ml or less.
(19) A method for preparing the compound described in any of above (1) to (18), which comprises reacting a compound of the formula(V): 
xe2x80x83wherein R6 is a leaving group and the other symbols are the same as defined above, an ester, or a salt thereof with a compound of the formula(IV): 
xe2x80x83wherein each symbol is the same as defined above, followed by optional deprotection.
(20) a compound of the formula(IV): 
xe2x80x83wherein each symbol is the same as defined above.
(21) the compound described in above(20) wherein R3 is hydrogen; R4 is xe2x80x94(CH2)3NRaCH3 wherein Ra is H or an amino-protecting group; and R5 is hydrogen,
(22) a pharmaceutical composition which contains a compound described in any of above (1) to (18).
(23) a composition for use as an antibacterial agent which contains a compound described in any of above (1) to (18).
(24) a method for preventing or treating bacterial infectious diseases, which comprises administering a compound described in any of above (1) to (18).
(25) use of the compound described in any of above (1) to (18) for preparing a composition for use as an antibacterial agent.